Stem Cells in Neural Development



The Desbordes Lab at the Institute for Developmental Genetics started its research activities in February 2012.

Our research focuses on the role of the environment and the cellular microenvironment during embryonic development and on disease onset and progression. We are particularly interested in neuronal differentiation and survival and in diseases resulting from dis-function of the nervous system.

INTRODUCTION

The number of people with diseases or disorders of the nervous system is increasing at alarming rates worldwide. Estimates suggest more than one out of 10 people older than 18 years suffer from depression, bipolar disorder, physiological neuropathies, or neurodegenerative diseases. It is well accepted that in addition to genetic predisposition, environmental factors have a major impact on the development of a disease. Systemic afflictions such as diabetes, chronic intoxications (through tobacco or alcohol consumption), or cancer can also lead to the development of disorders of the nervous system. Moreover, the modification of the microenvironment surrounding specific cell types, notably stem cells, can lead to aberrant cell division or differentiation and therefore can create a local ‘micro-disease’ that may lead to a generalized problem.




We use neuronal cells derived from embryonic stem cells (mouse and human) as well as other cells of the nervous system such as glia cells, to understand how the microenvironment and cells interplay (cell-cell adhesion, cell-extracellular matrix interactions and physical forces) can control embryonic development and how the deregulation of this interplay can affect the homeostasis of a tissue.

We are recreating these naturally occurring cellular processes in a dish, in order to generate an in vitro model system to decipher their underlying basic cellular and molecular mechanisms. We hope to elucidate disease development with the ultimate goal to apply our knowledge to regenerative medicine and for the screening and discovery of drugs with therapeutic potential.

We use a combination of molecular biology, glycobiology, genetics, biostatistics and high-throughput screening to:

  1. understand how key transcription factors regulate the cellular microenvironment to control tissue homeostasis 
  2. decipher the role of the extracellular matrix in neuronal differentiation and pathogenesis
  3. develop simple and robust cell-based assays for disease modelling and drug discovery using micropatterning

1. Understand how key transcription factors regulate the cellular microenvironment to control tissue homeostasis

Transcription factors govern the specification of cell identities. Although many transcriptional regulators of stem cell self-renewal and differentiation have been identified, it is still unclear how they influence the cellular microenvironment during cell self-renewal and cell-fate acquisition. We are investigating the role of key stem-cell regulators on extracellular matrix and tissue architecture. We have found that the stem cell factor Sox2 is able to induce a dramatic architectural modification in Schwann cell cultures, and that the changes are triggered by the extracellular matrix. We are now deciphering the exact mechanism by which this is happening and plan to interrogate how it is affected during the development of neuroblastoma.



2. Decipher the role of the extracellular matrix in neuronal differentiation and pathogenesis


The extracellular matrix is a complex composite of macromolecules involved in cellular support, cell migration, and cell-fate determination. Although the components of the extracellular matrix and their physical interactions with the cells are mostly well defined, it is not well understood how the extracellular matrix controls these processes. Our previous work has shown that glypicans, which are membrane-bound heparan-surface proteoglycans of the extracellular matrix, influence cell-fate decision by regulating the Hedgehog signaling pathway. In addition, there is growing evidence that glypicans play important roles in the development of several diseases, but the mechanisms by which this occurs are still unknown. We are investigating the role of glypicans during neuronal differentiation from pluripotent stem cells, specifically dopaminergic neurons, and the development of neurodegenerative diseases.

 

3. Develop simple and robust cell-based assays for disease modelling and drug discovery using micropatterning

The cellular microenvironment can exert mechanical forces to trigger signaling transduction cascades that regulate cell behavior. There is increasing evidence for mechanical forces to be sufficiently potent to control cell fate in a dish. Using controlled mechanics to influence cell-fate decisions in vitro has enormous potential as a robust platform for cell-based drug screening. We have pioneered the adaptation of human pluripotent stem cells to 384-well plate format for high-throughput screening. We are now combining this state-of-the-art technology with micropatterning in order to create optimal conditions for stem cell differentiation to specific cell types in a dish. In further combination with biophysical manipulations, we will generate cell-based assays to study diseases in a dish via induced-pluripotent cell reprogramming, as well as to identify drugs for personalized medicine. We also hope to provide a platform for the scientific community to test our models in an array of diseases or cell types of interest.




Finally, we use this innovative technology in combination with the use of specific cell types derived from human pluripotent stem cells to test the effect of environmental cues such as toxins, hypoxia, drugs, on disease development.

Staff recruitment
Our team is eager to get additional talented members (!!), ready to apply for outside funding.
Preference will be given to candidates with a stem cell biology background and/or experience in cell-based assay screening.
For postdocs, a good publication record during your graduate studies will be essential to obtain a fellowship.
Send your CV, letter of interest as well as two reference names to: